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Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis
Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, SP, 05403-000, Brazil
* Author to whom correspondence should be addressed.
Received: 6 September 2011; in revised form: 12 January 2012 / Accepted: 13 January 2012 / Published: 1 February 2012
Abstract: Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment.
Keywords: hemochromatosis; primary iron overload; HFE; high-resolution melting; HJV; molecular diagnostic
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Santos, P.C.J.L.; Krieger, J.E.; Pereira, A.C. Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis. Int. J. Mol. Sci. 2012, 13, 1497-1511.
Santos PCJL, Krieger JE, Pereira AC. Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis. International Journal of Molecular Sciences. 2012; 13(2):1497-1511.
Santos, Paulo C. J. L.; Krieger, Jose E.; Pereira, Alexandre C. 2012. "Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis." Int. J. Mol. Sci. 13, no. 2: 1497-1511.